Improved Algorithms for Macromolecular Structure Determination by cyro-EM

冷冻电镜大分子结构测定的改进算法

基本信息

批准号：
8761618
负责人：
Amit Singer
金额：
$ 33.78万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8761618
关键词：
Algorithms Area Biological Biological Process Classification Complex Computational algorithm Computer software Cryoelectron Microscopy Crystallization Data Data Set Detection Development Drug Design Electron Microscope Electron Microscopy Electrons Exhibits Failure Freezing Goals Heterogeneity Ice Image Individual Investigation Lead Linear Algebra Liquid substance Macromolecular Complexes Methods Molecular Molecular Conformation Molecular Structure Motion Names Nitrogen Noise Output Particle Size Performance Population Positioning Attribute Preparation Proteins Research Resolution Resort Rotation Sampling Signal Transduction Simulate Specimen Staining method Stains Structure Techniques Temperature Universities Validation Variant X-Ray Crystallography base computer framework cost heuristics image processing improved insight interest macromolecule novel novel strategies open source particle polypeptide programs protein structure public health relevance reconstruction signal processing structural biology success theories three dimensional structure

项目摘要

DESCRIPTION (provided by applicant): Single-particle electron cryomicroscopy (cryo-EM) is a method for observing the three- dimensional structures of large macromolecules. In cryo-EM the experimental data consist of noisy, random projection images of macromolecular "particles", and the problem is finding the 3D structure which is consistent with these images. The proposal aims to develop and apply to experimental data novel algorithms for solving two difficult mathematical problems posed by this technique of structural biology. First, classical cryo-EM reconstruction techniques assume that the particles are identical. However, in many datasets this assumption does not hold. Some molecules of interest have more than one conformational state. These structural variations are of great interest to biologists, as they provide insight int the functioning of the molecule. The first area of investigation in this project is the development of algorithmic and mathematical framework for determining structures associated with heterogeneous particle populations. The proposed algorithm is not only faster than existing techniques but is also mathematically provable to reveal the different conformations if the number of images is sufficiently large. Second, a major limiting factor for present cryo-EM studies is the particle size. Images of small particles are often too noisy for existing methods to provide valid three-dimensional reconstructions; although the images contain structural information, the assignment of orientations to the individual particles is unreliable. The second area of investigation focuses on developing a radical new approach for reconstruction of small particles without the need for determining particle orientations.

描述（由申请人提供）：单粒子电子冷冻显微镜（Cryo-EM）是一种观察大型大分子的三维结构的方法。在Cryo-EM中，实验数据由大分子“颗粒”的嘈杂，随机投影图像组成，问题是找到与这些图像一致的3D结构。该提案旨在开发并应用于实验数据的新算法，以解决这种结构生物学技术提出的两个困难的数学问题。首先，经典的冷冻EM重建技术假设颗粒是相同的。但是，在许多数据集中，这个假设不存在。某些感兴趣的分子具有多种构象状态。这些结构变化对生物学家非常有意义，因为它们提供了分子的功能。该项目的第一个调查领域是开发用于确定与异质粒子种群相关的结构的算法和数学框架的算法。所提出的算法不仅比现有技术更快，而且在数学上也可以证明，如果图像数量足够大，则可以揭示不同的构象。其次，当前冷冻EM研究的主要限制因素是粒径。小颗粒的图像通常太嘈杂，无法使用现有方法提供有效的三维重建；尽管图像包含结构信息，但分配给单个粒子的方向是不可靠的。第二个研究领域的重点是开发一种重建小颗粒的根本新方法，而无需确定粒子方向。